Several succinimide derivatives produce renal damage (acute tubular necrosis, interstitial nephritis) in man and/or animals. The proposed study is a continuation of our currently funded project (AM31210) and will investigate (a) the structural requirements for nephrotoxicity, (b) the identity and site of formation of toxic metabolites, (c) potential cellular mechanisms of toxicity, and (d) the interactive potential of succinimides with nephrotoxic and hepatotoxic agents. Nephrotoxicity will be monitored in acute and subacute structural comparative studies by measuring a variety of urinary excretion parameters (volume, content, pH, osmolality), in vitro accumulation of organic ions by renal cortical slices and histology (light and electron microscopy). The identity and site of formation of metabolites will be examined using enzyme induction and inhibition studies, glutathione depletion studies, structural modification of nephrotoxic succinimides and by determining the nephrotoxic potential of known or suspected succinimide metabolites (in vivo, in vitro and isolated perfused kidney). If maleimide or other nephrotoxic metabolites are produced, they will be quantitated and identified using TLC, HPLC and GC/MS. Cellular mechanisms of toxicity will be examined in enzyme induction, calcium mediation of nephrotoxicity, lipid peroxidation, pro benecid modulation of nephrotoxicity and correlation of fungicidal activity with nephrotoxicity studies. The effect of various parameters (species, strain, sex and age) on succinimide-induced nephropathy also will be examined. The interactive potential of 3,5-NDPS with nephro- and hepatotoxins will be examined to determine if a nephrotoxic succinimide (3,5-NDPS) can alter the nephro- and/or hepatotoxic properties of selected toxins. In addition, the ability of these toxins to potentiate/reduce 3,5-NDPS-induced nephropathy also will be investigated. The results obtained from these studies will further our knowledge in the area of chemically-induced renal disease. The identification of maleimide metabolites would mean the discovery of a new class of toxic biotransformation products. Future studies will attempt to more precisely define the cellular mechanisms of succinimide-induced nephropathy, the nephrotoxic potential of related chemical species, and the mechanisms of toxic interactions between succinimides and other chemicals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031210-05
Application #
3229957
Study Section
Toxicology Study Section (TOX)
Project Start
1983-04-01
Project End
1991-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Marshall University
Department
Type
Schools of Medicine
DUNS #
036156615
City
Huntington
State
WV
Country
United States
Zip Code
25701
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Rankin, Gary O; Hong, Suk-kil; Anestis, Dianne K (2008) Nephrotoxicity induced by N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid in male and female Fischer 344 rats. J Appl Toxicol 28:867-73
Rankin, Gary O; Anestis, Dianne K; Valentovic, Monica A et al. (2007) Nephrotoxicity induced by the R- and S-enantiomers of N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and their sulfate conjugates in male Fischer 344 rats. Toxicology 240:38-47
Rankin, Gary O; Hong, Suk K; Anestis, Dianne K et al. (2002) Effect of three n-acetylamino acids on N-(3,5-dichlorophenyl)succinimide (NDPS) and ndps metabolite nephrotoxicity in Fischer 344 rats. J Toxicol Environ Health A 65:539-56
Rankin, G O; Hong, S K; Anestis, D K et al. (2001) In vitro nephrotoxicity induced by N-(3,5-dichlorophenyl)succinimide (NDPS) metabolites in isolated renal cortical cells from male and female Fischer 344 rats: evidence for a nephrotoxic sulfate conjugate metabolite. Toxicology 163:73-82
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Hong, S K; Anestis, D K; Kennedy, S et al. (1999) Effect of sulfation substrates/inhibitors on N-(3,5-dichlorophenyl)succinimide nephrotoxocity in Fischer 344 rats. J Toxicol Environ Health A 57:47-62
Hong, S K; Anestis, D K; Brown, P I et al. (1999) Effect of glucuronidation substrates/inhibitors on N-(3,5-dichlorophenyl)succinimide nephrotoxicity in Fischer 344 rats. Toxicology 132:43-55
Hong, S K; Anestis, D K; Ball, J G et al. (1999) Sodium sulfate potentiates N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) nephrotoxicity in the Fischer 344 rat. Toxicology 138:165-74
Hubbard, J L; Noe 2nd, O; Egermayer, M et al. (1999) Nephrotoxic potential of N-(3,5-dichloro-4-fluorophenyl)succinimide in Fischer 344 rats: comparison with N-(3,4,5-trichlorophenyl)succinimide. Toxicology 132:127-37

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